Alcohol abuse and dependence have been linked clinically with negative affect and depression. Variations in the clinical presentation of alcoholism and depression have complicated diagnoses of "co-morbid depression," "dual diagnosis," "abstinence depression" and other negative affect symptoms, although it is generally agreed that alcohol dependent patients experience depression when they stop drinking. Further, the co-occurrence of negative affect or depression symptoms with alcoholism predicts more severe disease and a poor response to treatment. Prevailing theories of depression include the classic monoamine hypothesis as well as emerging molecular theories involving CREB gene transcription, neurotrophic pathways, and hippocampal neurogenesis. To date, however, no preclinical studies have addressed the neurobiological mechanisms of alcohol-induced depression. We have discovered that abstinence from chronic voluntary alcohol drinking is associated with increased immobility in the Porsolt swim test (PST), a validated model of depression-like behavior, in mice. This behavioral pathology is completely blocked by chronic administration of the antidepressant desipramine. Studies in Specific Aim 1 of this application will utilize this animal model to further characterize the relationship between chronic alcohol drinking and the emergence of depression-like behavior during abstinence. Specific Aim 2 will determine the efficacy and dose-response of several antidepressant medications to gain insight into potential therapeutic mechanisms. Specific Aim 3 of this project is to conduct an integrative analysis of molecular adaptations that are associated with 1) alcohol-induced depression and 2) antidepressant treatment. In support of this approach, we have discovered that alcohol-induced depression-like behavior is associated with significant decreases in p-CREB and BDNF expression and neurogenesis in the dentate gyrus of the hippocampus, each of which has been hypothesized to underlie depression. We have also found that desipramine reverses the alcohol- induced reduction in p-CREB and BDNF specifically in the dentate gyrus. Finally, Specific Aim 4 of this application is to manipulate CREB phosphorylation and BDNF levels in the hippocampus to determine if molecular adaptations in this important brain region functionally regulate alcohol-induced depression. This project has the potential to elucidate factors that lead to co-morbid depression in alcoholism, identify effective medications, and characterize underlying neurobiological adaptations that are associated (or dissociated) with alcohol-induced depression and its treatment. This information may be of major significance for the development of therapies that may benefit depression and alcoholism, as well as establishing the molecular basis of the interaction of these two mental diseases.